Darunavir, also known as [(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-carbamic acid (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester, is represented by the structural Formula I:

Darunavir is an inhibitor of the HIV protease belonging to the class of hydroxyethyl amino sulfonamides and is available as its ethanolate solvate under the name PREZISTA in the form of Eq75 mg, 150 mg, 400 mg and 600 mg base oral tablets and Eq100 mgbase/ml oral suspension.
Darunavir was first generically disclosed in U.S. Pat. No. 5,843,946 (“the 946 patent”) and specifically disclosed in U.S. Pat. No. 6,248,775 (“the 775 patent”). The '775 patent further discloses a process for the preparation of darunavir active moiety, [(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-carbamic acid of Formula II by reacting N-[3S-benzyloxycarbonylamino-2R-hydroxy-4-phenyl]-N-isobutylamine with 4-nitrobenzene sulfonyl chloride in presence of triethyl amine followed by hydrogenating the resultant nitro compound with palladium carbon. The '775 patent does not disclose any enabling disclosure for the preparation of darunavir (hexahydrofuranyl ester of Formula II). The process disclosed in the '775 patent is schematically represented as follows:

The '775 patent process involves simultaneous reduction of the nitro moiety and CBz deprotection in intermediate nitro compound results in a highly exothermic reaction that generates unwanted side reactions with the result that decreasing the product selectivity.
The first synthesis of darunavir was described in A. K. Ghosh et al. Bioorganic & Medicinal Chemistry Letters 8 (1998) 687-690, which is herein incorporated by reference. The synthesis includes reacting azido epoxide with isobutylamine and treatment of the resultant azido alcohol with p-nitrobenzene sulfonyl chloride to afford nitro compound. The nitro compound was hydrogenated with Palladium catalyst and then resultant amine compound was transformed to darunavir upon reaction with hexahydrofuro[2,3-b]furan-3-yl derivative in methylene chloride in the presence of 3 equivalents of triethylamine at 23° C. for 12 hours.
The process disclosed in the A. K. Ghosh et al is not suitable for large-scale production because it involves hazardous azide compounds; thus it requires utmost care to use. The process disclosed in the A. K. Ghosh et al is schematically represented as follows:

To overcome the difficulties associated with the A. K. Ghosh et al, alternate processes were disclosed, for example U.S. Pat. No. 7,772,411 (“the '411 patent”) discloses the preparation of darunavir using boc-epoxide instead of azido epoxide as starting material. The '411 patent process involves a) reaction of boc epoxide with isobutylamine, b) introducing the p-nitrobenzene sulfonyl chloride c) reducing the nitro moiety d) deprotecting the boc protection and e) coupling the amine compound with hexahydrofuro[2,3-b]furan-3-yl derivative in a mixture of ethyl acetate and acetonitrile and in the presence of triethyl amine and methyl amine in aqueous ethanol.
Although the '411 patent process involves boc-epoxide instead of hazardous azido epoxide, the process still have difficulty to operate on large scale as it involves multistage synthesis hence the overall yield is limited to about 50%. The process disclosed in the '411 patent is schematically represented as follows:

PCT Publication No. WO 2010/023322 (“the '322 publication”) discloses an alternate process of darunavir by a) reaction of boc-epoxide with N-benzyl-isobutylamine, b) deprotecting the amine protecting group c) coupling the amine compound with hexahydrofuro[2,3-b]furan-3-yl derivative d) removing the N-benzyl group e) introducing the p-nitrobenzene sulfonyl chloride and f) reducing the nitro moiety. The '322 publication process also involves multistep synthesis, this leads to an increase in the manufacturing cycle time. The process disclosed in the '322 publication process is schematically represented as follows:

PCT Publication No. WO 2011/051978 (“the '978 publication”) discloses an alternative process of darunavir by introducing furanyl compound before the nitro group reduction. This publication mention that the synthesis of darunavir by coupling of Formula II with hexahydrofuro[2,3-b]furan-3-yl derivative very likely leads to formation of impurities, viz., Impurity A and Impurity B.

The process disclosed in the '978 publication process is schematically represented as follows:

PCT Publication No. WO 2011/048604 (“the '604 publication”) discloses a process for preparation of darunavir having bisfuranyl Impurity of Formula C less than 0.1% by coupling the 4-Amino-N-((2R,3S)-3-amino-2-hydroxy-4-phenyl)-N-(isobutyl)benzene sulfonamide with (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol derivative using N-methyl-2-pyrrolidinone as reaction solvent. The '604 publication further disclosed amorphous darunavir having particle size D50 of approximately 50 micrometers and D90 of approximately 100 to 180 micrometers.

PCT Publication No. WO 2011/092687 (“the '687 publication”) discloses a process for preparation of darunavir by following scheme:

PCT Publication No. WO 2013/011485 (“the 485 publication”) discloses a process preparation of darunavir by following scheme:

Darunavir can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
Several pseudopolymorphic forms of darunavir are described in the literature, for example U.S. Patent Application No. 2005/0250845 disclosed darunavir amorphous Form, Form A (ethanolate), Form B (hydrate), Form C (methanolate), Form D (acetonate), Form E (dichloromethanate), Form F (ethylacetate solvate), Form G (1-ethoxy-2-propanolate), Form H (anisolate), Form I (tetrahydrofuranate), Form J (isopropanolate) and Form K (mesylate) of darunavir.
Journal of Molecular Biology, Vol 338, No 2, 23 Apr. 2004, pages 341-352 discloses the preparation of darunavir as white amorphous solid.
Amorphous Darunavir preparation was described in several ways in the literature, for example in WO2011/048604, WO2011/073993, WO 2011/083287, WO 2011/145099 & IN 2548/CHE/2009. Further WO2010/086844 describes the amorphous form of Darunavir with IR spectrum with characteristic peaks about 1454 and 1369 cm−1.
The processes for preparation of darunavir described in the above literature have certain drawbacks as it involves: a) harsh reaction conditions for example nitro reduction using palladium carbon and hydrogen gas may lead to decomposition of sensitive carbamate linkage and further requires special pressure equipments for carrying out the synthesis, b) use of multiple solvents and bases during the introduction of furanyl ring makes the process not viable for large scale manufacturing.
Further darunavir obtained from the above processes was not satisfactory from purity point of view. Darunavir synthetic procedures as described in the art contained relatively large amounts of impurities, for example, when replicating the process of the '411 patent resulted in the elevation of bisfuranyl impurities. Extensive purification procedures are required in order to limit the impurities to less than the required as per regulatory guidelines; results low product yield thereby making the process quite expensive.
Hence there remains a need for an improved process to prepare darunavir, particularly amorphous form of darunavir, which is cost effective, industrially viable, and provide darunavir substantially free of impurities.